Approximately 30 percent of HIV-positive patients have a history of injection drug abuse that frequently involves the use of opiates. Because of the substantial evidence that both endogenous and exogenous opioids and opiate-abuse modulate immune function, and also that opiates augment HIV-1 replication in vitro, there continues to be a extended debate and considerable research has been aimed at understanding whether opiates alter HIV-1 infection and progression to AIDS. The present application is designed to address this important question in SHIV KU- 2/macaque model of AIDS. This model of HIV/AIDS has been successfully used in our laboratory to study the pathogenesis of the virus, effect of anti retroviral drugs and evaluation of different candidate vaccines. We will use morphine sulfate to establish opiate-dependence in macaques by intramuscular injection, and infect these macaques along with control animals with highly pathogenic SHIV KU-2. These experiments will determine, whether morphine treatment alters the expression of mu-opioid receptor (MOR) in monkeys, and whether morphine- dependence enhances intensity of SHIV KU-2 replication in vivo and accelerates the onset of clinical disease in SHIV/macaque model of HIV/AIDS. We will also examine the effect of morphine treatment on in vivo apoptosis of T cells. In another series of experiments we will examine the effect of morphine addiction on the development and persistence of virus-specific immune responses that will help us understand effect of drug-abuse on the development of immune responses, induced by a vaccine. We will immunize morphine-dependent and control macaques with a live virus vaccine that has been shown to confer solid protection against SHIV-induced AIDS. The virus-specific immune response in these two groups will be compared for the strength and duration. These animals will be challenged with pathogenic SHIV KU-2 to determine whether morphine-dependence compromises the live vaccine-induced protection.